Wallace received widespread notice in 2002 while with the Iowa State Cyclones in a play known affectionately to some as "The Run," in which he traversed back to the 32 yard line before running it in for a 12-yard touchdown versus Texas Tech. While quarterbacking the Iowa State Cyclones in 2001 and 2002, he threw 26 touchdowns and 27 interceptions.

In 2006, Wallace started in four games as quarterback after an injury to Hasselbeck's right knee. Under his leadership, the team won two games and lost two. His passer rating was 76.2 for the 2006 season, passing just under 1000 yards, throwing 8 touchdowns and 7 interceptions.

In 2007, Mike Holmgren began using Wallace as a wide receiver in limited formations. By week seven Wallace had caught two passes, run two end arounds, and thrown an incomplete pass on an end around option pass.

In 2008, Wallace started two pre-season games at quarterback and had good statistics against the Minnesota Vikings and Oakland Raiders. After injuries to wide receivers that hurt the Seattle Seahawks, Wallace was moved to that position, but strained a calf in his first game.

After the injury of Matt Hasselbeck, he returned as a starter in week seven of the season at Tampa Bay, where the team lost 20-10. The next week, he led his team to a 34-13 win over San Francisco. In week 9, Wallace threw for the longest touchdown pass in Seattle Seahawks franchise history with a 90-yard completion to Koren Robinson in the Seahawks' first play from scrimmage. However, the Seahawks lost to the Philadelphia Eagles, 26-7. Wallace played again in the 21-19 road loss to the Miami Dolphins in week ten. Hasselbeck was cleared by team doctors to play and was the starter again for week 11. Because of another injury to Hasselbeck, Wallace started in week 14 against the New England Patriots, where he threw 20 completions in 28 attempts for 212 yards and three touchdowns. His passer rating for the game was 128.9. He also ran for 47 yards on three carries. However, a lost fumble by Wallace late in the fourth quarter led to a 24-21 Seahawks loss. The following week, he captured his second win as a starter as the Seahawks beat the St. Louis Rams 23-20 at the Edward Jones Dome. Hasselbeck returned from injury, but Wallace remained the starter for the rest of the season. Wallace had another good performance in a victory against the New York Jets in week 16, but lost to the eventual NFC champion Arizona Cardinals in week 17.

On March 8, 2010 Wallace was traded to the Cleveland Browns for the 7th round, 209th pick in the 2011 NFL Draft. With this trade, Wallace was reunited with his former Seattle coach and then-Browns president Mike Holmgren. He made his regular season debut September 12, 2010 after starting quarterback Jake Delhomme injured his ankle during a week 1 loss to the Tampa Bay Buccaneers. He would go on to start the next four games before suffering a high ankle sprain during week 5 versus the Atlanta Falcons.[1] On March 3, 2011, Wallace signed a three-year deal with the Browns.[2] Wallace was released by the Cleveland Browns after the conclusion of the 2012 preseason.

On August 22, 2013, he signed a one-year deal with the San Francisco 49ers.[5] A week later on August 29, 2013 he asked for his release.[6] He later said that (contrary to some news reports) he was not retiring, but had decided to leave the 49ers because he felt they were not giving him a chance to make the team, and had signed him only to pressure their principal backup quarterback, Colt McCoy, to accept a pay cut.[7]

On September 2, 2013, Wallace signed with the Green Bay Packers.[8] He first played for the Packers on November 4, 2013 after an injury to the left shoulder of Aaron Rodgers in the first quarter of the Monday night game against the Chicago Bears. His first start for the Packers was on Sunday, November 10, 2013 against the Philadelphia Eagles. During the game's opening drive, Wallace suffered a season ending groin injury and had to leave the game. He was replaced by quarterback Scott Tolzien,[9] who made his first regular season NFL appearance.[10]

Seneca Wallace was the first ever African-American to start a game as quarterback for the Green Bay Packers.